Study 20 flashcards on Aplastic Anaemia & Bone Marrow Failure: Causes, Pathogenesis & Treatment with OmpathStudy. Quick, focused revision for Kenyan medical...
Q1. What is pancytopenia? List causes of decreased bone marrow production
Answer: Pancytopenia → reduction in all three cell lines: red cells, white cells, platelets Causes of decreased production: Aplasia → reduced haemopoietic stem cells Acute leukaemia, myelodysplasia, myeloma Infiltration → lymphoma, solid tumours, TB Megaloblastic anaemia PNH Myelofibrosis Haemophagocytic syndrome Splenomegaly
Q2. Define aplastic anaemia. List secondary causes
Answer: Definition → pancytopenia resulting from hypoplasia of the bone marrow Secondary causes: Ionizing radiation → accidental, radiotherapy, radioactive isotopes Chemicals → benzene, organophosphates, DDT, pesticides, ecstasy Drugs → busulfan, melphalan, cyclophosphamide (regular); chloramphenicol, sulphonamides, gold (occasional) Viruses → viral hepatitis (non-A, non-B, non-C, non-G), EBV Autoimmune → SLE Transfusion-associated GVHD Thymoma → more usually causes red cell aplasia
Q3. Explain the pathogenesis of aplastic anaemia
Answer: Substantial reduction in haemopoietic pluripotential stem cells Remaining stem cells have a fault OR immune reaction is directed against them → Stem cells unable to divide and differentiate → bone marrow fails to populate Idiopathic acquired type → oligoclonal CD8+ cytotoxic T cells destroy haemopoietic tissue Clonal haemopoiesis with somatic mutations of PIGA, ASXL1, DNMT3A present in ~50% of cases
Q4. Describe Fanconi anaemia — genetics, features, diagnostic test, and treatment
Answer: Inheritance → autosomal recessive Age → presents 3–14 years; ~10% develop AML Features: Growth retardation Skeletal defects → microcephaly, absent radii or thumbs Renal tract defects → pelvic or horseshoe kidney Skin → hyper and hypopigmentation Sometimes learning disability Genetics → 16 genes (FANC A–Q); FANCD1 = BRCA2; genes involved in DNA repair via ubiquitination of FANCD2 Diagnostic test → DEB test (elevated chromosomal breakage after diepoxybutane — DNA cross-linking agent) Treatment → androgens and/or SCT; mild conditioning, no irradiation (cells sensitive to DNA damage)
Q5. Describe Dyskeratosis Congenita and Diamond-Blackfan Anaemia
Answer: Dyskeratosis Congenita: Sex-linked Features → nail atrophy, skin atrophy, pulmonary fibrosis, cirrhosis, osteoporosis, cancer risk Mutations in DKC1 (dyskerin) or TERC → affect telomere length maintenance Diamond-Blackfan Anaemia: Congenital pure red cell aplasia — only red cells affected Autosomal recessive Mutations in ribosome synthesis genes Features → neutropenia, skeletal abnormalities, short stature, hepatic impairment Risk of transformation to MDS or AML
Q6. What are the clinical features of aplastic anaemia? What is notably absent?
Answer: Most common type → idiopathic acquired (≥ two-thirds of cases) Peak incidence → 10–25 years and 60 years ; more frequent in Asia Onset → insidious or acute Anaemia → fatigue, pallor Thrombocytopenia → bruising, bleeding gums, epistaxis, menorrhagia, retinal haemorrhage Neutropenia → mouth/throat infections; generalized life-threatening infections Notably absent → lymph nodes, liver, and spleen are NOT enlarged
Q7. List the laboratory criteria for aplastic anaemia. What defines severe and very severe?
Answer: At least 2 of: Hb <100 g/L — normochromic normocytic or macrocytic; very low reticulocytes Neutrophils <1.5 × 10⁹/L Platelets <50 × 10⁹/L Severe → neutrophils <0.5, platelets <20, reticulocytes <20 × 10⁹/L, marrow cellularity <25% Very severe → neutrophils <0.2 × 10⁹/L Bone marrow → haemopoietic tissue replaced by fat ( 75%); mainly lymphocytes and plasma cells; megakaryocytes absent/severely reduced No abnormal cells in peripheral blood
Q8. How is aplastic anaemia diagnosed? What must be excluded?
Answer: Distinguish from other causes of pancytopenia PNH must be excluded → flow cytometry for CD55 and CD59 In older patients → exclude hypoplastic myelodysplasia (clonal cytogenetic/molecular changes suggest MDS) Cytogenetic and molecular analysis → exclude inherited forms
Q9. List the specific treatments for aplastic anaemia with key details for each
Answer: ATG (Antithymocyte Globulin) → benefit in 50–60%; given with ciclosporin → up to 80% respond to combined ATG + ciclosporin; corticosteroids given short-term for serum sickness Ciclosporin → effective alone in older patients; valuable in combination Alemtuzumab (anti-CD52) → ~50% response; used after ATG failure Eltrombopag (TPO mimetic) → stimulates platelets; may improve all cell lines Androgens → beneficial in some; virilization, liver damage, cholestatic jaundice side effects SCT → favoured in <35 years with HLA-matched sibling; cure rate up to 80% ; conditioning = cyclophosphamide + ciclosporin (no irradiation) G-CSF → minor responses only; no sustained improvement
Q10. Define PNH. What is the pathogenesis?
Answer: Definition → rare acquired clonal disorder of marrow stem cells with deficient GPI anchor synthesis Clinical triad → chronic intravascular haemolysis + venous thrombosis + bone marrow failure Pathogenesis: Acquired mutation in PIG-A gene (X chromosome) → essential for GPI anchor formation GPI-linked proteins CD55 and CD59 absent from cell surface Loss of DAF (CD55) and MIRL (CD59) → red cells unprotected from complement → chronic intravascular haemolysis
Q11. List the clinical features of PNH and its main clinical problem
Answer: Haemosiderinuria → constant feature → causes iron deficiency → worsens anaemia Absent haptoglobins → free Hb damages kidneys + removes nitric oxide → dysphagia and pulmonary hypertension Main clinical problem → venous thrombosis → portal, hepatic, mesenteric veins; also strokes and MI Intermittent abdominal pain → mesenteric vein thrombosis Diagnosis → flow cytometry showing loss of CD55 and CD59 (replaced Ham test)
Q12. How is PNH treated?
Answer: Eculizumab (humanized anti-C5 antibody) → inhibits terminal complement → reduces haemolysis, transfusion needs, and thrombosis risk Iron therapy → for iron deficiency Long-term anticoagulation → warfarin Immunosuppression → can be useful Allogeneic SCT → definitive treatment Disease usually remits spontaneously; median survival 10 years May transform to MDS or AML
Q13. Define red cell aplasia. Distinguish transient from chronic forms
Answer: Definition → anaemia with normal WBC and platelets + grossly reduced/absent erythroblasts in marrow Transient → parvovirus B19 → infects red cell precursors via P antigen → 5–10 days aplasia → dangerous in sickle cell disease and hereditary spherocytosis Chronic congenital → Diamond-Blackfan syndrome Chronic acquired → idiopathic OR associated with: thymoma, SLE, lymphoma, CLL , T-cell large granular lymphocytosis, viral infections, drugs (azathioprine, co-trimoxazole) Treatment → corticosteroids, rituximab, ciclosporin, azathioprine, ATG
Q14. Describe Schwachman-Diamond Syndrome
Answer: Rare autosomal recessive Exocrine pancreatic dysfunction → invariable feature (key distinguishing point) Varying degrees of cytopenia → especially neutropenia Skeletal abnormalities, hepatic impairment, short stature Risk of transformation to MDS or AML Mutations in gene SD involved in ribosome synthesis
Q15. Describe congenital dyserythropoietic anaemias (CDAs) — key features and types
Answer: Hereditary refractory anaemias → ineffective erythropoiesis + erythroblast multinuclearity Normal WBC and platelets; low reticulocytes despite increased marrow cellularity Jaundice, bone marrow expansion, splenomegaly, iron overload CDA Type I → CDAN1 gene mutation CDA Type II (HEMPAS) → SEC23B gene → positive acidified serum lysis test with some sera but NOT patient's own serum Alpha-interferon → induces remission in some cases
Q16. Describe osteopetrosis — pathogenesis, features, and treatment
Answer: Failure of bone resorption by osteoclasts Inheritance → recessive or dominant Bones dense but brittle → fractures common Marrow space reduced → leucoerythroblastic anaemia Liver and spleen enlarged Death from bone marrow failure is usual SCT → offers chance of cure
Q17. List the key MCQ associations for aplastic anaemia and related syndromes
Answer: Absent thumbs/radii → Fanconi anaemia DEB test → diagnostic for Fanconi anaemia FANCD1 = BRCA2 Exocrine pancreatic dysfunction + cytopenia → Schwachman-Diamond syndrome Nail + skin atrophy + aplasia → Dyskeratosis congenita (DKC1/TERC mutations) Parvovirus B19 → via P antigen → transient red cell aplasia; dangerous in sickle cell/spherocytosis GPI anchor defect → PNH (PIG-A mutation, X-linked) PNH diagnosed by → flow cytometry (CD55, CD59 loss) PNH treated with → eculizumab (anti-C5) PNH main clinical problem → venous thrombosis Haemosiderinuria → constant feature of PNH HEMPAS → CDA Type II (SEC23B gene) Osteopetrosis → failure of osteoclast bone resorption → SCT = cure
Q18. List the key MCQ associations for treatment and severity in aplastic anaemia
Answer: Most common type → idiopathic acquired Pathogenesis → oligoclonal CD8+ T cell autoimmune destruction Peak incidence → 10–25 years and 60 years Lymph nodes, liver, spleen → NOT enlarged Very severe → neutrophils <0.2 × 10⁹/L SCT favoured → <35 years with HLA-matched sibling; cure rate up to 80% ATG + ciclosporin response rate → up to 80% Alemtuzumab → anti-CD52; used after ATG failure
Q19. Explain why blood products in aplastic anaemia must be leucodepleted
Answer: Prevents alloimmunisation → patient developing antibodies against donor white cell antigens Prevents grafting of live donor lymphocytes → could cause transfusion-associated GVHD Antifibrinolytic agent (tranexamic acid) also used → reduces haemorrhage in severe prolonged thrombocytopenia
Q20. Summarise the high-yield points for PNH pathogenesis and why venous thrombosis occurs
Answer: PIG-A mutation → no GPI anchor → CD55 and CD59 absent from red cells, WBCs, and platelets CD55 (DAF) + CD59 (MIRL) normally protect cells from complement Their absence → complement attacks red cells → intravascular haemolysis Haemolysis → free Hb scavenges nitric oxide (NO) from smooth muscle → NO deficiency → platelet aggregation and thrombosis Platelets also lack CD59 → activated by complement → thrombosis in portal, hepatic, mesenteric veins This is why venous thrombosis is the main clinical problem